ABSTRACT Organelle contacts are emerging as critical signaling platforms in metazoan cells. In non-neuronal cells, many of the important physiological functions played by mitochondria such as Ca2+ uptake and lipid biogenesis require a specialized structural and functional interface with the smooth endoplasmic reticulum (ER). Recent data from non-neuronal cells support a model whereby mitochondrial Ca2+ uptake can only occur upon Ryanodine and/or IP3 receptors-mediated Ca2+ release from the ER at sites of ER-mitochondria contacts, where Ca2+ transiently reaches high enough concentrations to open the mitochondrial calcium uniporter (MCU). Therefore, interfaces between organelles, such as ER and mitochondria, are emerging as critical platforms for many biological responses in eukaryotic cells. However, the function of ER-mitochondria coupling in developing and adult neurons is currently unknown despite recent ultrastructural evidence (including our own results) showing that numerous direct contacts between ER and mitochondria can be observed in dendrites in vivo. In addition, changes in the extent of ER-mitochondria contacts have been reported in various models of neurodegenerative diseases such as Alzheimer?s disease and Parkinson?s disease. However the pathophysiological impact of these changes in ER-mitochondria contacts is largely unknown. The goal of this proposal is to explore the role of ER-mitochondria interface in neuronal development, synaptic integration and circuit function. The major roadblock to study the function of ER-mitochondria coupling in any cell types including neurons is due to the absence of a molecular toolkit required to manipulate this organelle interface. We recently identified Pdzd8 as an ER protein playing a critical role in ER-mitochondria tethering (Hirabaryashi et al. Science 2017). We found that in cortical neurons, PDZD8 is required for Ca2+ uptake by mitochondria following synaptically-induced Ca2+-release from ER and thereby regulates cytoplasmic Ca2+ dynamics in dendrites. Our results identify PDZD8 as the first, critical ER- mitochondria tethering protein in metazoan cells and uncover a novel role for ER-mitochondria coupling in the regulation of dendritic Ca2+ dynamics in mammalian neurons. We hypothesize that PDZD8-dependent ER-mitochondria tethering plays critical roles in regulating cytoplasmic Ca2+ homeostasis in dendrites and might contribute to the formation of branch-specific Ca2+ ?domains? regulating synaptic integration and therefore in the dendritic properties underlying circuit function. Overall, our project will test, with unprecedented relevance, the role of a new biological interface, ER-mitochondria contacts, in dendritic Ca2+ dynamics, synaptic integration and circuit function in vivo.